Suppository base composition

ABSTRACT

A suppository base composition comprising 5-80% by weight of polyethylene glycol, 5-80% by weight of triglyceride of fatty acid having 6-22 carbon atoms and 5-80% by weight of a specifically limited alkylene oxide derivative has a melting point of 30°-60° C., a compatibility with both of a polar drug component and a non-polar drug component, and can provide suppositories having excellent moldability and storage stability.

This is a continuation of application Ser. No. 198,581 filed Oct. 20,1980, now U.S. Pat. No. 4,368,185.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to a suppository base composition.

(2) Description of the Prior Art

A suppository is smaller than other medicinal preparations for internaluse in the amount of drug component to be decomposed by the action ofacid, alkali, digestive enzymes and the like in the digestive fluid, andfurther does not cause gastroenteric troubles. Particularly, asuppository has merit in that it can be easily dosed to children.Moreover, when a systemic dosage of a medicine by injection causesserious ill effects, the ill effects can be decreased by a local dosageof a suppository only to the diseased portion, and further the humanbody can be free from the pain at the injecton.

There are mainly used two kinds of suppository bases of polyethyleneglycol (hereinafter, abbreviated as PEG) and triglyceride (hereinafter,abbreviated as TG) of fatty acid at present.

Both PEG and TG are excellent suppository bases, but when a suppositoryis produced by the use of highly hydrophilic PEG, only a highly polardrug component, which dissolves in PEG or disperses uniformly therein,can be used. On the other hand, when a suppository is produced by theuse of TG, which is highly lipophilic, only a non-polar drug componentwhich dissolves in TG or disperses uniformly therein can be used.Moreover, PEG and TG have no compatibility with each other, andtherefore they cannot be used in admixture, and it accordingly isdifficult to use a polar drug component in combination with a non-polardrug component.

Further, in the suppository using TG, the suppository is melted by thebody temperature to absorb the drug component into the human body.Therefore, the melting point of the suppository is set to a temperaturenear the body temperature, and the suppository possesses poor strengthat high temperatures. Therefore, it is necessary to store thesuppository in a cold and dark place in order to prevent deformation ofshape, and the suppository has a risk of melting during itstransportation.

The inventors have made various investigations in order to producesuppository bases free from these drawbacks, and found out that aspecifically limited alkylene oxide derivative is excellent as asuppository base and is able to mix PEG and TG, and invented a novelsuppository base containing these three components.

SUMMARY OF THE INVENTION

The feature of the present invention is to provide a suppository basecomposition comprising 5-80% by weight of PEG having an averagemolecular weight of 200-20,000, 5-80% by weight of TG of fatty acidhaving 6-22 carbon atoms and 5-80% by weight of a compound having thefollowing general formula (1), whose hydroxyl groups may be partly orwholly esterified:

    B[(AO).sub.a (C.sub.2 H.sub.4 O).sub.b H].sub.n            ( 1)

wherein B represents a residue of a compound having 1-8 active hydrogenatoms, A reprresents C₃ H₆ or C₄ H₈ alone or in admixture, a representsan integer of 15-50, b represents an integer of 20-200, n represents aninteger of 1-8, and having an average molecular weight of at least 2,500per one functional group.

DESCRIPTION OF THE PREFERRED EMBODIMENT

PEGs to be used in the present invention are ones having an averagemolecular weight of 200-20,000.

TGs of fatty acid having 6-22 carbon atoms to be used in the presentinvention are TGs of caproic acid, caprilic acid, capric acid, lauricacid, myristic acid, palmitic acid, stearic acid, oleic acid, arachicacid, behenic acid and the like. These TGs are used alone or inadmixture.

The compounds having the above described general formula (1) arecompounds obtained by adding a given amount of alkylene oxide to acompound having 1-8 active hydrogen atoms.

The compounds having 1-8 active hydrogen atoms include methyl alcohol,ethyl alcohol, butyl alcohol, octyl alcohol, lauryl alcohol, myristylalcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, isostearylalcohol, dimeric acohols formed by a Guerbet process, ethylene glycol,propylene glycol, butylene glycol, hexylene glycol, dodecane diol,hexadecane diol, octadecane diol, glycerine, trimethylolethane,trimethylolpropane, 1,3,5-pentane triol, erythritol, pentaerythritol,diglycerine, triglycerine, dipentaerythritol, sorbitol, sorbitan,sorbide, glucose, fructose, mannose, xylose, methyl glucoside,trehalose, sucrose, ethylenediamine and the like.

The addition amount of alkylene oxides to the above described compoundhaving 1-8 active hydrogen atoms is such that propylene oxide, butyleneoxide or tetrahydrofuran or mixture thereof is added to the compound inan amount of 15-50 moles per functional group of the compound andethylene oxide is added to the compound in an amount of 20-200 moles perfunctional group of the compound. Moreover, it is necessary that theresulting addition product having the above described general formula(1) has an average molecular weight of at least 2,500 per functionalgroup. When the addition amount of the alkylene oxides is smaller thanthe above described amount, the resulting addition product having theabove described general formula (1) can not be able to mix homogeneouslyPEG and TG. When the addition amount exceeds the above described amount,the addition product has an excessively high melting point and viscosityand is difficult to handle in the formulation of a small sizesuppository. The compound having the general formula (1) has such anexcellent property that the compound can dissolve or disperse moreeasily than PEG and TG, and that the compound can mix PEG and TG in anoptimal mixing ratio. The compound having the general formula (1) has amelting point of 10°-70° C., and when PEG and TG to be compounded withthe compound are properly selected, suppository base compositions havingan optimal melting point can be produced.

The suppository base composition of the present invention is ahomogeneous mixture consisting of 5-80% by weight, respectively, of theabove described three components of PEG, TG and the compound having thegeneral formula (1). When the amount of any one of the above describedthree components exceeds 80% by weight, the drawbacks of the respectivethree components appear. When the amount of any one of the threecomponents is smaller than 5% by weight, the mixing effect of the threecomponents does not appear. Particularly, when the amount of thecompound having the general formula (1) is smaller than 5% by weight,PEG can not be homogeneously mixed with TG, and separates from TG. It ispreferable that the ethylene oxide chain of the compound having thegeneral formula (1) occupy 40-90% of the total molecular weight of thatcompound; and that the compound of general formula (1) have an averagemolecular weight of 3,000-9,000 per functional group. It is alsopreferable that the residue B be a residue of an alcohol or glycolhaving 1-22 carbon atoms.

The suppository base composition of the present invention contains botha hydrophilic component and a lipophilic component, and therefore thecomposition can be used as a base for both a polar drug component and anon-polar drug component, and suppository base compositions having amelting point of 30°-60° C. can be produced. Therefore, the suppositorybase composition can be widely used, and the resulting suppository isvery excellent in the moldability and storage stability.

The suppository base composition of the present invention may containwater, propylene glycol, glycerine, propylene glycol fatty acid ester,sucrose fatty acid ester, sorbitan fatty acid ester, polyoxethylenealkyl ether, polyoxyethylene polyhydric alcohol fatty acid ester andoil-soluble polyoxyalkylene glycol derivative in order to lower itsviscosity during production, to adjust its melting point, to improve itslubricating property at the insertion of the suppository into the humanbody and to promote the liberation of the drug component.

The following examples are given for the purpose of illustration of thisinvention and are not intended as limitations thereof. In the examples,"%" means % by weight.

EXAMPLE 1

Suppository base compositions shown in the following Table 2 wereprepared by the use of PEG, TG and a compound having the general formula(1) shown in the following Table 1, and a compatibility test of thecompositions was carried out.

Test method and evaluation method

Into a beaker of 300 ml capacity is charged 100 g of a samplecomposition, which is stirred at 60° C. until the composition becomeshomogeneous. When the composition has become homogeneous, the stirringis stopped, and the beaker is cooled to 20° C. to solidify thecomposition.

The composition is evaluated according to the following standard.

o . . . homogeneously solidified composition

x . . . two or more separated layers or inhomogeneously solidifiedcomposition.

The tested compositions and the test results are shown in Table 2.

It can be seen from Table 2 that all the suppository base compositionsof the present invention, which are prepared by the use of the compoundhaving the general formula (1), have homogeneously solidified, and havegood compatibility.

                                      TABLE 1                                     __________________________________________________________________________    Compound used in the test                                                     __________________________________________________________________________    1. PEG*.sup.5 average molecular weight                                           PEG #300    300                                                               PEG #400    400                                                               PEG #1540  1500                                                               PEG #4000  3000                                                               PEG #6000  9000                                                            2. TG         composition of alkyl groups                                        TG - A     C.sub.8 : 85%, C.sub.10 : 15%                                      TG - B     C.sub.12 : 50%, C.sub.14 : 23%, C.sub.16 : 14%, C.sub.18 :                    13%                                                                TG - C     C.sub.12 : 42%, C.sub.14 : 18%, C.sub.16 : 17%, C.sub.18 :                    23%                                                                TG - D     C.sub.12 : 68%, C.sub.14 : 10%, C.sub.16 : 11%, C.sub.18 :                    11%                                                             3. Compound having the                                                           general formula (1)                                                           C - 1      C.sub.16 H.sub.33 O(C.sub.3 H.sub.6 O).sub.30 (C.sub.2                        H.sub.4 O).sub.25 H                                                C - 2      C.sub.18 H.sub.37 O(C.sub.3 H.sub.6 O).sub.30 (C.sub.2                        H.sub.4 O).sub.40 H                                                C - 3      C.sub.24 H.sub.49 O(C.sub.3 H.sub.6 O).sub.25 (C.sub.2                        H.sub.4 O).sub.50 H                                                C - 4*.sup.1                                                                             P[(C.sub.3 H.sub.6 O).sub.17 (C.sub.2 H.sub.4 O).sub.50                       H].sub.2                                                           C - 5      P[(C.sub.3 H.sub.6 O).sub.25 (C.sub.2 H.sub.4 O).sub.70                       H].sub.2                                                           C - 6      P[(C.sub.3 H.sub.6 O).sub.35 (C.sub.2 H.sub.4 O).sub.100                      H].sub.2                                                           C - 7      P[(C.sub.4 H.sub.8 O).sub.2 (C.sub.3 H.sub.4 O).sub.60                        COC.sub.11 H.sub.28 ].sub.2                                        C - 8*.sup.2                                                                             D[(C.sub.3 H.sub.6 O).sub.40 (C.sub.2 H.sub.4 O).sub.120                      H].sub.2                                                           C - 9*.sup.3                                                                             G[(C.sub.3 H.sub.6 O).sub.30 (C.sub.2 H.sub.4 O).sub.70                       H].sub.3                                                           C - 10*.sup.4                                                                            S[(C.sub.3 H.sub.6 O).sub.30 (C.sub.2 H.sub.4 O).sub.80                       H].sub.6                                                        4. Other compound                                                                D - 1      C.sub.16 H.sub.33 O(C.sub.2 H.sub.4 O).sub.25 H                    D - 2      C.sub.15 H.sub.37 O(C.sub.3 H.sub.6 O).sub.30 (C.sub.2                        H.sub.4 O).sub.3 H                                                 D - 3*.sup.1                                                                             P[(C.sub.3 H.sub.6 O).sub.10 (C.sub.2 H.sub.4 O).sub.15                       H].sub.2                                                           D - 4      polyoxyethylene(20)-sorbitan monooleate                            D - 5      polyoxyethylene(70)-pentaerythritol tristearate                    D - 6      glycerine monostearate                                             D - 7      propylene glycol                                                   D - 8      water                                                           __________________________________________________________________________     Note-                                                                         *.sup.1 P means propyleneglycol                                               *.sup.2 D means dodecanediol residue                                          *.sup.3 G means glycerine residue                                             *.sup.4 S means sorbitol residue                                              *.sup.5 PEGs #300, #400, #1540, #4000 and #6000 are trademarks of PEGs        sold by Nippon Oil and Fats Company Ltd.                                 

                                      TABLE 2                                     __________________________________________________________________________    Results of compatibility test                                                             Suppository base composition                                                                Compound                                                                      having                                                                        the general            Melting                             Test                                                                             PEG     TG      formula (1)                                                                           Other compound point                               No.                                                                              Compound                                                                            % Compound                                                                            % Compound                                                                            % Compound                                                                            %  Evaluation                                                                          (°C.)                 __________________________________________________________________________    Composition                                                                          1    #6000                                                                             30                                                                              TG-B  30  C-1 40                                                                              --    -- o     48                           according to                                                                         2    "   30                                                                              "30     C-2                                                                             40  --                                                                              --    o  52                                 the present                                                                          3    "   35                                                                              "     35  C-3 30                                                                              --    -- o     50                           invention                                                                            4    "   30                                                                              "     20  C-4 50                                                                              --    -- o     46                                  5    "   30                                                                              "     20  C-5 50                                                                              --    -- o     50                                  6    "   40                                                                              "     40  C-6 20                                                                              --    -- o     55                                  7    "   40                                                                              "     30  C-7 30                                                                              --    -- o     50                                  8    "   30                                                                              "     30  C-8 40                                                                              --    -- o     54                                  9    "   30                                                                              "     30  C-9 40                                                                              --    -- o     52                                  10   "   30                                                                              "     30   C-10                                                                             40                                                                              --    -- o     52                                  11    #400                                                                             35                                                                              TG-C  35  C-6 30                                                                              --    -- o     46                                  12    #400                                                                             35                                                                              TG-D  35  C-6 30                                                                              --    -- o     46                                  13   #6000                                                                             25                                                                              TG-D   5  C-2 70                                                                              --    -- o     52                                  14   #6000                                                                              5                                                                              TG-D  25  C-5 70                                                                              --    -- o     50                                        #300                                                                             20                                                                              TG-C  30  C-3 29                                                   15                         --    -- o     50                                       #1540                                                                             20          C-6 10                                                                        C-2 20                                                   16    #400                                                                             30                                                                              TG-A  30        --    -- o     43                                                       C-6 20                                                         #400                                                                             20                                                                              TG-D  40  C-2 20                                                   17                         --    -- o     45                                       #4000                                                                             10          C-8 10                                                         #400                                                                             20                                                                              TG-C  35  C-2 20                                                   18                         D-1   5  o     45                                       #4000                                                                             10          C-6 10                                                         #400                                                                             30                                                                              TG-B   7  C-6 20                                                   19                         D-2   8  o     47                                       #4000                                                                             30           C-10                                                                              5                                                         #400                                                                              5                                                                              TG-C  68  C-2  5                                                   20                         D-3   2  o     45                                       #4000                                                                              5          C-6 15                                                   21   #1540                                                                             35                                                                              TG-D  40  C-6 20                                                                              D-4   5  o     55                                       #4000                                                                             30                                                                              TG-C  25  C-2 20                                                   22                         D-5   10 o     52                                                       C-6 15                                                   23   #4000                                                                             30                                                                              TG-C  30  C-6 35                                                                              D-6   5  o     52                                  24   "   30                                                                              "     30  "   35                                                                              D-7   5  o     48                                  25   "   30                                                                              "     30  "   35                                                                              D-8   5  o     46                           Comparative                                                                          26   #6000                                                                             25                                                                              TG-B  25  --  --                                                                              D-1   50 x     --                           Composition                                                                          27   "   " "     "   --  --                                                                              2     "  x     --                                  28   "   " "     "   --  --                                                                              3     "  x     --                                  29   "   " "     "   --  --                                                                              4     "  x     --                                  30   "   " "     "   --  --                                                                              5     "  x     --                                  31   #6000                                                                             15                                                                              TG-B  15  --  --                                                                              D-1   70 x     --                                  32   "   " "     "   --  --                                                                              2     "  x     --                                  33   "   " "     "   --  --                                                                              3     "  x     --                                  34   "   " "     "   --  --                                                                              4     "  x     --                                  35   "   " "     "   --  --                                                                              5     "  x     --                           __________________________________________________________________________

EXAMPLE 2

A mixture of 5 g of a drug component and 75 g of a suppository basecomposition shown in the following Table 3 was melted at 70° C. Themelted mixture, after being fully stirred, was filled in a containerpack of 2.5 g capacity for a suppository. The storage stability of theresulting suppositories was measured after the suppositories were keptat 5° C., 20° C. or 35° C. for 2 weeks; or kept at 5° C. and at 40° C.on alternate days for two weeks, and was evaluated according to thefollowing standard:

o . . . Original homogeneous state was maintained.

x . . . Crystals of drug component grew, and the suppository becameinhomogeneous.

xx . . . Almost all the drug component was separated.

The following Table 3 shows the results of the test.

It can be seen from Table 3 that the suppository of the presentinvention always maintains a homogeneous state within the temperaturerange of 5°-70° C. and has a good storage stability.

                                      TABLE 3                                     __________________________________________________________________________    Storage stability test for suppository                                                           70° C.                                                                 (at the           5° C. and 40° C. on        Drug component                                                                         Base composition                                                                        formulation)                                                                         5° C.                                                                     20°C.                                                                      35° C.                                                                     alternate days                           __________________________________________________________________________    Indomethacin                                                                           *No. 11 composition                                                                     homogeneous                                                                          o  o   o   o                                                 in Table 2                                                                              transparent                                                                   liquid                                                              *No. 18 composition                                                                     homogeneous                                                                          o  o   o   o                                                 in Table 2                                                                              transparent                                                                   liquid                                                              PEG #1540 75%                                                                           homogeneous                                                                          x  x   x   x                                                 PEG #4000 25%                                                                           transparent                                                                   liquid                                                              TG-B    50%                                                                             substantially                                                                        o  o   x   xx                                                TG-C    50%                                                                             homogeneous                                                                   dispersion                                                 Acetylsalicylic                                                                        *No. 12 composition                                                                     homogenous                                                                           o  o   o   o                                        acid     in Table 2                                                                              transparent                                                                   liquid                                                              *No. 20 composition                                                                     homogenous                                                                           o  o   o   o                                                 in Table 2                                                                              transparent                                                                   liquid                                                              PEG  #400 10%                                                                           homogenous                                                                           x  o   o   o                                                 PEG #4000 90%                                                                           transparent                                                                   liquid                                                              TG-B    40%                                                                             substantially                                                                        o  o   o   xx                                                TD-D    60                                                                              homogeneous                                                                   dispersion                                                 Ergosterol                                                                             *No. 6 composition                                                                      homogeneous                                                                          o  o   o   o                                                 in Table 2                                                                              transparent                                                                   liquid                                                              *No. 16 composition                                                                     homogeneous                                                                          o  o   o   o                                                 in Table 2                                                                              transparent                                                                   liquid                                                              REG #1540 80%                                                                           substantially                                                                        x  x   o   o                                                           homogeneous                                                         Reg #6000 20%                                                                           transparent                                                                   liquid                                                              TG-C    50%                                                                             substantially                                                                        o  o   x   xx                                                TG-D    50%                                                                             homogeneous                                                                   dispersion                                                 __________________________________________________________________________     Note:                                                                         Among the base compositions, base compositions indicated by the mark * ar     those according to the present invention, and base compositions having no     mark are comparative compostions.                                        

What is claimed is:
 1. A molded, storage-stable suppository basecomposition, stable in a temperature range of from 5 degrees C. to 70degrees C., comprising 5-80% by weight of polyethylene glycol having anaverage molecular weight of 200-20,000, 5-80% by weight of triglycerideof fatty acid having 6-22 carbon atoms and 5-80% by weight of a compoundhaving the following general formula (1), whose hydroxyl group may bepartly or wholly esterified,

    B[(AO).sub.a (C.sub.2 H.sub.4 O).sub.b H].sub.n            ( 1)

wherein B represents a residue of an alcohol or polyol having 1-8 activehydrogen atoms, A represents C₃ H₆ or C₄ H₈ alone or in admixture, arepresents an integer of 15-50, b represents an integer of 20-200 and nrepresents an integer of 1-8, and having an average molcular weight ofat least 2,500 per one functional group, said suppository compositionbeing substantially homogeneous in liquid and solid states.